A variety of organophosphorus compounds are known to be useful as anthelmintics for controlling internal parasites in the gastrointestinal tract of warm-blooded animals. In particular, dimethyl 2,2-dichlorovinyl phosphate (DDVP; dichlorvos) and related beta-halovinyl phosphates are effective anthelmintics: U.S. Pat. Nos. 3,166,472, 3,536,791, 3,553,322; including thiono-analogs of DDVP: U.S. Pat. No. 3,740,429.
Also, it is known that when a dialkyl beta-halovinyl phosphate is administered to a prospective mother mammal, the vitality of the foetus or foeti and the new-born young is increased: U.S. Pat. No. 3,507,956.
Some of these compounds, in particular dichlorvos, are of interest for oral administration to warm-blooded animals to control fly larvae which feed on the excreted feces of the animals. In this use of these compounds, it is essential that a sufficient amount of the drug be passed with the feces to control the fly larvae feeding on the excreted feces.
For the sake of brevity, all of these medically useful organophosphorus compounds will be hereinafter described and referred to generically as "the drug" or as "drugs", and these terms are intended to include mixtures of such compounds, as well as the individual compounds.
These drugs are toxic to mammals, so that to be able to take advantage of their desirable properties without injury or adverse effect upon the animal to be treated, it is necessary to administer them as formulations, the character of the formulation being such that during its passage through the gastrointestinal tract of the animal the effective dosage of the drug, but no more, is released, and the drug is released at such a point, or points, in the gastrointestinal tract as to provide the desired effect.
Where the drug is to be used as a fecal larvicide, it must be formulated in a similar manner, to protect the drug during passage of the formulation through the animal, yet make the drug available to control fly larvae in the excreted feces.
As disclosed in the patents that have been mentioned herein, and other patents, such as U.S. Pat. Nos. 3,318,769, 3,076,744 and 3,223,513, and Canadian patents Nos. 701,470 and 755,683, such drugs commonly have been formulated for such uses by incorporating them in water-insoluble resin matrices from which the drugs slowly and continuously diffuse to the surface of the matrix, there becoming available to liquids in the gastrointestinal tract of the animal being treated and/or in its excreted feces in amounts which give the beneficial effects, without injury or adverse effect upon the animal being treated. However, in practice such formulations have been found to have several substantial drawbacks. Such formulations are most efficiently administered, as a matter of practical animal husbandry, in the animal's feed. Frequently, the feed merchant or farmer has to store feed for considerable period of time before it is used. Since the dosage of the formulation is quite small, compared to the volume of feed, the formulation must be in the form of small particles, which can be uniformly distributed throughout the mass of the feed. This physical form--high surface area-to-volume ratio--raises problems which these formulations fail to solve: the organophosphorus drugs tend to be lost, some because of their volatility and all because they are sensitive to water such as moisture in the air and in the feed, decomposing hydrolytically to inactive compounds. Possibly, other materials in the feed also can cause decomposition of these drugs. Further, it is often desirable that the treated feed be in the form of pellets or crumbs. Steam is often used to aid in forming such pellets or crumbs, and steam readily and rapidly decomposes such organophosphorus drugs. Consequently, when in the form of high surface area-to-volume ratio particles, such resin formulations do not sufficiently protect the drug from loss due to volatility, and from the effect of water and/or other materials in the feed. Consequently, the drug can be lost during processing of the treated feed and, further, during the storage of the treated feed at ambient temperatures, the content of the drug in the treated feed declines relatively rapidly with time, so that such resin formulations therefore often are not entirely suitable for administration of such organophosphorus drugs in the feed of the host animal being treated. Further, such compositions release the drug continuously, which may be undesirable from the point of view of optimum utilization of the drug with minimum risk of toxic effects. Also, the rate of drug release from such compositions can be varied only to a limited degree.